Throughout this application various publications are referred to in parenthesis. Citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Pregnane X Receptor (PXR) (NR1I2; also termed SXR, PAR) is the primary xenobiotic sensor in human and mammalian tissues. It responds to a wide range of structurally- and chemically-distinct ligands that range from small lipophilic drugs (e.g., rifampicin) to potentially toxic bile acids as well as cholesterol metabolites (1-10, 31). A large number of commonly encountered environmental toxins (e.g., phthalates), chemotherapy (e.g., taxanes), drug vehicles (e.g., DEHP), co-medications (e.g., dexamethasone), and herbals (e.g., curcumin, hyperforin) can activate PXR. To date, only three PXR antagonist have been described: ketoconazole (and related azoles; 11), suphoraphane (12) and ecteinascidin-743 (ET-743) (13). Ketoconazole was first described as a PXR antagonist by Takeshita et al. (14), and was subsequently shown to disrupt the binding of coregulators (including both coactivators and corepressors) to the surface of PXR in an agonist-dependent fashion (15). In the presence of the established PXR activator rifampicin, ketoconazole and related azoles were shown to prevent the activation of the receptor both in cell-based assays as well as in a humanized PXR mouse model (16). Ketoconazole binds to at least a region outside the ligand-binding pocket. The revertant activation function 2 (AF-2) region double mutant of PXR (T248E/K277Q) activates with rifampicin but is not inhibited by ketoconazole (11, 17).
The promiscuous activation of PXR by natural substances and xenobiotics has been implicated as a mechanism that accelerates the metabolism of affected drugs, which leads to unanticipated adverse drug reactions and lack of efficacy. PXR activation in the gut can lower drug bioavailability. Recent data also supports a major role for PXR activation in controlling (decreasing) the transport of drugs across blood brain barrier (32), underscoring PXR's role in drug delivery to the brain and limiting the effectiveness of therapeutics on primary brain tumors or brain metastases. Therefore, in the context of cancer therapeutics, controlling PXR activation serves to improve both drug metabolism and delivery. Thus, there is a need for new, non-toxic antagonists of PXR activation as well as a further understanding of how PXR inhibition can benefit treatment of diseases such as cancer.